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Recent Results on the Development of Fetal Immune System: Self, Epigenetic Regulation, Fetal Immune Responses

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Maternal Fetal Transmission of Human Viruses and their Influence on Tumorigenesis

Abstract

In vertebrates there are two major classes of defence systems acting against infectious microorganisms. Innate immune systems use constitutively expressed receptors recognizing conserved, repetitive structures on different classes of pathogens. Such unique molecules are usually absent from host cells, which ensures self-nonself discrimination. Adaptive immune systems ensure protective immunity by generating a vast repertoire of “anticipatory” receptors via somatic diversification of receptor encoding genes. Thus, in principle, adaptive immune systems are capable to recognize any unique molecular conformation (antigen). Antigen specificity, lymphoid tissue organization and memory are important innovations of adaptive immune systems. Because lymphoid cells can specifically recognize, in addition to the antigenic determinants of pathogens, “self” antigens (autoantigens) as well, multiple mechanisms evolved to curb destructive autoimmune reactions. In the absence of unique molecular signatures of “self”, a clonal selection process eliminates immature lymphocytes receiving “strong” signals via their receptors from certain surrounding (i.e. “self”) molecules in the central lymphoid organs (central tolerance). In the thymus, the nuclear protein AIRE (autoimmune regulator) switches on transcription of silent, tissue specific genes randomly, permitting presentation of the corresponding “self” antigens by medullary thymic epithelial cells to newly formed thymocytes (T cells). Cell fate decisions depend on the avidity of T cell receptor to the presented “self” antigen and antigen presentation (MHC) molecule: low affinity binding results in a positive selection (maturation to helper and cytotoxic T cells, migration to the periphery), whereas moderate-avidity interaction yields regulatory T cells that express the master transcription factor Foxp3 and display an anergic phenotype at the periphery. During pregnancy the maternal immune system adapts to the presence of fetal (paternal) alloantigens by activating multiple, redundant mechanisms of peripheral tolerance.

On the course of B lymphocyte development epigenetic regulatory mechanisms coordinate the expression of lymphoid specific gene sets and ensure relocation of the recombining and non-recombining receptor gene segments (V, D, and J) to the suitable nuclear subcompartments. “Pioneer” transcription factors change the local and regional epigenetic marks of the genome, resulting in a new “epigenome” and transcriptional program. Epigenetic marks (DNA methylation, histone modifications, Polycomb/Trithorax complexes) can be transmitted from cell generation to cell generation (epigenetic memory). Induction of another master regulator or regulatory network by suitable signals may change, however, the epigenome, creating thereby a new cellular identity and phenotype. In humans, such processes do not result, however, in a fully developed immune system even at birth. This immaturity and immunodeficiency is compensated during intrauterine life by the transplacental passage of maternal high avidity IgG antibodies to the fetus and after birth by the complex antiinfective components present in human milk.

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References

  • Agrawal A, Eastman QM, Schatz DG (1998) Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 394:744–751. doi:10.1038/29457

    PubMed  CAS  Google Scholar 

  • Aït-Azzouzene D, Caucheteux S, Tchang F, Wantyghem J, Moutier R, Langkopf A, Gendron MC, Kanellopoulos-Langevin C (2001) Transgenic major histocompatibility complex class I antigen expressed in mouse trophoblast affects maternal immature B cells. Biol Reprod 65:337–344. doi:10.1095/biolreprod65.2.337

    PubMed  Google Scholar 

  • Alhajjat AM, Durkin ET, Shaaban AF (2010) Regulation of the earliest immune response to in utero hematopoietic cellular transplantation. Chimerism 1:61–63. doi:10.4161/chim.1.2.13147

    PubMed  Google Scholar 

  • Aluvihare VR, Kallikourdis M, Betz AG (2004) Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 5:266–271. doi:10.1038/ni1037

    PubMed  CAS  Google Scholar 

  • Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–1401. doi:10.1126/science.1075958

    PubMed  CAS  Google Scholar 

  • Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, eneropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20–21. doi:10.1038/83713

    PubMed  CAS  Google Scholar 

  • Bernstein RM, Schluter SF, Bernstein H, Marchalonis JJ (1996) Primordial emergence of the recombination activating gene 1 (RAG1): sequence of the complete shark gene indicates homology to microbial integrases. Proc Natl Acad Sci U S A 93:9454–9459. doi:10.1073/pnas.93.18.9454

    PubMed  CAS  Google Scholar 

  • Blomen VA, Boonstra J (2011) Stable transmission of reversible modifications: maintenance of epigenetic information through the cell cycle. Cell Mol Life Sci 68:27–44. doi:10.1007/s00018-010-0505-5

    PubMed  CAS  Google Scholar 

  • Byrne JA, Stankovic AK, Cooper MD (1994) A novel subpopulation of primed T cells in the human fetus. J Immunol 152:3098–3106

    PubMed  CAS  Google Scholar 

  • Carotta S, Holmes ML, Pridans C, Nutt SL (2006) Pax5 maintains cellular identity by repressing gene expression throughout B cell differentiation. Cell Cycle 5:2452–2456. doi:10.4161/cc.5.21.3396

    PubMed  CAS  Google Scholar 

  • Chirico G (2005) Development of the immune system in neonates. J Arab Neonatol Forum 2:5–11

    Google Scholar 

  • Cooper MD, Alder MN (2006) The evolution of adaptive immune systems. Cell 124:815–822. doi:10.1016/j.cell.2006.02.001

    PubMed  CAS  Google Scholar 

  • Darrasse-Jèze G, Klatzmann D, Charlotte F, Salomon BL, Cohen JL (2006) CD4 + CD25+ regulatory/suppressor T cells prevent allogeneic fetus rejection in mice. Immunol Lett 102:106–109. doi:10.1016/j.imlet.2005.07.002

    PubMed  Google Scholar 

  • de la Rosa M, Rutz S, Dorninger H, Scheffold A (2004) Interleukin-2 is essential for CD4 + CD25+ regulatory T cell function. Eur J Immunol 34:2480–2488. doi:10.1002/eji.200425274

    PubMed  Google Scholar 

  • Decker T, Pasca di Magliano M, McManus S, Sun Q, Bonifer C, Tagoh H, Busslinger M (2009) Stepwise activation of enhancer and promoter regions of the B cell commitment gene Pax5 in early lymphopoiesis. Immunity 30:508–520. doi:10.1016/j.immuni.2009.01.012

    PubMed  CAS  Google Scholar 

  • Degner SC, Wong TP, Jankevicius G, Feeney AJ (2009) Developmental stage-specific recruitment of cohesin to CTCF sites throughout immunglobulin loci during B lymphocyte development. J Immunol 182:44–48

    PubMed  CAS  Google Scholar 

  • Derbinski J, Gäbler J, Brors B, Tierling S, Jonnakuty S, Hergenhahn M, Peltonen L, Walter J, Kyewski B (2005) Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 202:33–45. doi:10.1084/jem.20050471

    PubMed  CAS  Google Scholar 

  • Derbinski J, Pinto S, Rösch S, Hexel K, Kyewski B (2008) Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc Natl Acad Sci U S A 105:657–662. doi:10.1073/pnas.0707486105

    PubMed  CAS  Google Scholar 

  • Dreyfus DH (2009) Paleo-immunology: evidence consistent with insertion of a primordial herpes virus-like element in the origins of acquired immunity. PLoS One 4:e5778. doi:10.1371/journal.pone.0005778

    PubMed  Google Scholar 

  • Du Pasquier L (2000) The phylogenetic origin of antigen-specific receptors. Curr Top Microbiol Immunol 248:160–185

    PubMed  Google Scholar 

  • Erlebacher A (2010) Immune surveillance of the maternal/fetal interface: controversies and implications. Trends Endocrinol Metab 21:428–434. doi:10.1016/j.tem.2010.02.003

    PubMed  CAS  Google Scholar 

  • Ferguson BJ, Alexander C, Rossi SW, Liiv I, Rebane A, Worth CL, Wong J, Laan M, Peterson P, Jenkinson EJ, Anderson G, Scott HS, Cooke A, Rich T (2008) AIRE’s CARD revealed, a new structure for central tolerance provokes transcriptional plasticity. J Biol Chem 283:1723–1731. doi:10.1074/jbc.M707211200

    PubMed  CAS  Google Scholar 

  • Fichtelius KE (1967) The mammalian equivalent to the bursa Fabricii of birds. Exp Cell Res 46:231–234

    Google Scholar 

  • Fitzsimmons SP, Bernstein RM, Max EE, Skok JA, Shapiro MA (2007) Dynamic changes in accessibility, nuclear positioning, recombination, and transcription at the Igκ locus. J Immunol 179:5264–5273

    PubMed  CAS  Google Scholar 

  • Földes G, Liu A, Badiger R, Paul-Clark M, Moreno L, Lendvai Z, Wright JS, Ali NN, Harding SE, Mitchell JA (2010) Innate immunity in human embryonic stem cells: comparison with adult human endothelial cells. PLoS One 5:e10501. doi:10.1371/journal.pone.0010501

    PubMed  Google Scholar 

  • Forestier F, Daffos F, Catherine N, Renard M, Andreux JP (1991) Developmental hematopoiesis in normal human fetal blood. Blood 77:2360–2363

    PubMed  CAS  Google Scholar 

  • Fugmann SD, Messier C, Novack LA, Cameron RA, Rast JP (2006) An ancient evolutionary origin of the Rag1/2 gene locus. Proc Natl Acad Sci U S A 103:3728–3733. doi:10.1073/pnas.0509720103

    PubMed  CAS  Google Scholar 

  • Fujii Y, Okumura M, Inada K, Nakahara K, Matsuda H (1992) CD45 isoform expression during T cell development in the thymus. Eur J Immunol 22:1843–1850. doi:10.1002/eji.1830220725

    PubMed  CAS  Google Scholar 

  • Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, Busslinger M (2004) Pax5 induces V-to-DJ rearrangements and locus contraction of the immungloblin heavy-chain gene. Genes Dev 18:411–422. doi:10.1101/gad.291504

    PubMed  CAS  Google Scholar 

  • Gao H, Lukin K, Ramírez J, Fields S, Lopez D, Hagman J (2009) Opposing effects of SWI/NSF and Mi-2/NuRD chromatin remodeling complexes on epigenetic reprogramming by EBF and Pax5. Proc Natl Acad Sci U S A 106:11258–11263. doi:10.1073/pnas.0809485106

    PubMed  CAS  Google Scholar 

  • Gershon RK, Kondo K (1971) Infectious immunological tolerance. Immunology 21:903–914

    PubMed  CAS  Google Scholar 

  • Giambra V, Volpi S, Emelyanov AV, Pflugh D, Bothwell AL, Norio P, Fan Y, Ju Z, Skoultchi AI, Hardy RR, Frezza D, Birshtein BK (2008) Pax5 and linker histone H1 coordinate DNA methylation and histone modifications in the 3’ regulatory region of the immunoglobulin heavy chain locus. Mol Cell Biol 28:6123–6133. doi:10.1128/MCB.00233-08

    PubMed  CAS  Google Scholar 

  • Glimcher LH, Murphy KM (2000) Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev 14:1693–1711. doi:10.1101/gad.14.14.1693

    PubMed  CAS  Google Scholar 

  • Godfrey VL, Wilkinson JE, Russell LB (1991) X-linked lymphoreticular disease in scurfy (sf) mutant mouse. Am J Pathol 138:1379–1387

    PubMed  CAS  Google Scholar 

  • Goriely S, Van Lint C, Dadkhah R, Libin M, De Wit D, Demonté D, Willems F, Goldman M (2004) A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells. J Exp Med 199:1011–1016. doi:10.1084/jem.20031272

    PubMed  CAS  Google Scholar 

  • Grindebacke H, Stenstad H, Quiding-Järbrink M, Waldenström J, Adlerberth I, Wold AE, Rudin A (2009) Dynamic development of homing receptor expression and memory cell differentiation of infant CD4 + CD25 high regulatory T cells. J Immunol 183:4360–4370. doi:10.4049/jimmunol.0901091

    PubMed  CAS  Google Scholar 

  • Guerin LR, Prins JR, Robertson SA (2009) Regulatory T cells and immune tolerance in pregnancy: a new target for infertility treatment? Hum Reprod Update 15:517–535. doi:10.1093/humupd/dmp004

    PubMed  CAS  Google Scholar 

  • Hansen JD, McBlane JF (2000) Recombination-activating genes, transposition, and the lymphoid-specific combinatorial immune system: a common evolutionary connection. Curr Top Microbiol Immunol 248:111–135

    PubMed  CAS  Google Scholar 

  • He T, Hong SY, Huang L, Xue W, Yu Z, Kwon H, Kirk M, Ding SJ, Su K, Zhang Z (2011a) Histone acetyltransferase p300 acetylates Pax5 and strongly enhances Pax5-mediated transcriptional activity. J Biol Chem 286:14137–14145. doi:10.1074/jbc.M110.176289

    PubMed  CAS  Google Scholar 

  • He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L, Sun Y, Li X, Dai Q, Song CX, Zhang K, He C, Xu GL (2011b) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333(6047):1303–1307. doi:10.1126/science.1210944

    PubMed  CAS  Google Scholar 

  • Hesslein DG, Pflugh DL, Chowdhury D, Bothwell AL, Sen R, Schatz DG (2003) Pax5 required for recombination of transcribed, acetylated IgH V segments. Genes Dev 17:37–42. doi:10.1101/gad.1031403

    PubMed  CAS  Google Scholar 

  • Hewitt SL, Farmer D, Marszalek K, Cadera E, Liang HE, Xu Y, Schlissel MS, Skok JA (2008) Association between the Igk and Igh immunoglobulin loci mediated by the 3’ Igk enhancer induces ‘decontraction’ of the Igh locus in pre-B cells. Nat Immunol 9:396–404. doi:10.1038/ni1567

    PubMed  CAS  Google Scholar 

  • Hiom K, Melek M, Gellert M (1998) DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 94:463–470. doi:10.1016/S0092-8674(00)81587-1

    PubMed  CAS  Google Scholar 

  • Holladay SD, Smialowicz RJ (2000) Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure. Environ Health Perspect 108:463–473. doi:10.2307/3454538

    PubMed  CAS  Google Scholar 

  • Holt PG, Jones AC (2000) The development of the immune system during pregnancy and early life. Allergy 55:688–697. doi:10.1034/j.1398-9995.2000.00118.x

    PubMed  CAS  Google Scholar 

  • Hunt DWC, Huppertz HI, Jiang HJ, Petty RE (1994) Studies of human cord blood dendritic cells: evidence for functional immaturity. Blood 12:4333–4343

    Google Scholar 

  • Ichiyama K, Yoshida H, Wakabayashi Y, Chinen T, Saeki K, Nakaya M, Takaesu G, Hori S, Yoshimura A, Kobayashi T (2008) Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat. J Biol Chem 283:17003–17008. doi:10.1074/jbc.M801286200

    PubMed  CAS  Google Scholar 

  • Ingram RM, Valeaux S, Wilson N, Bouhlel MA, Clarke D, Krüger I, Kulu D, Suske G, Philipsen S, Tagoh H, Bonifer C (2011) Differential regulation of sense and antisense promoter activity at the Csf1R locus in B cells by the transcription factor PAX5. Exp Hematol 39:730–740.e2. doi:10.1016/j.exphem.2011.04.004

    PubMed  CAS  Google Scholar 

  • Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science doi:10.1126/science.1210597

    Google Scholar 

  • James E, Chai JG, Dewchand H, Macchiarulo E, Dazzi F, Simpson E (2003) Multiparity induces priming to male-specific minor hisocompatibility antigen HY, in mice and humans. Blood 102:388–393. doi:10.1182/blood-2002-10-3170

    PubMed  CAS  Google Scholar 

  • Jhunjhunwala S, van Zelm MC, Peak MM, Murre C (2009) Chromatin architecture and the generation of antigen receptor diversity. Cell 138:435–448. doi:10.1016/j.cell.2009.07.016

    PubMed  CAS  Google Scholar 

  • Jiang SP, Vacchio MS (1998) Multiple mechanisms of peripheral T cell tolerance to the fetal “allograft”. J Immunol 160:3086–3090

    PubMed  CAS  Google Scholar 

  • Johnnidis JB, Venanzi ES, Taxman DJ, Ting JP, Benoist CO, Mathis DJ (2005) Chromosomal clustering of genes controlled by the aire transcription factor. Proc Natl Acad Sci U S A 102:7233–7238. doi:10.1073/pnas.0502670102

    PubMed  CAS  Google Scholar 

  • Johnson K, Pflugh DL, Yu D, Hesslein DG, Lin KI, Bothwell AL, Thomas-Tikhonenko A, Schatz DG, Calame K (2004) B cell-specific loss of histone 3 lysine 9 methylation in the V(H) locus depends on Pax5. Nat Immunol 5:853–861. doi:10.1038/ni1099

    PubMed  CAS  Google Scholar 

  • Jones AC, Miles EA, Warner JO, Colwell BM, Bryant TN, Warner JA (1996) Fetal peripheral blood mononuclear cell proliferative responses to mitogenic and allergenic stimuli during gestation. Pediatr Allergy Immunol 7:109–116. doi:10.1111/j.1399-3038.1996.tb00117.x

    PubMed  CAS  Google Scholar 

  • Jones CA, Vance GH, Power LL, Pender SL, Macdonald TT, Warner JO (2001) Costimulatory molecules in the developing human gastrointestinal track: A pathway for fetal allergen priming. J Allergy Clin Immunol 108:235–241. doi:10.1067/mai.2001.117178

    PubMed  CAS  Google Scholar 

  • Jones CA, Jolloway JA, Warner JO (2002) Fetal immune responsiveness and routes of allergic sensitization. Pediatr Allergy Immunol 13(Suppl 15):19–22. doi:10.1034/j.1399-3038.13.s.15.6.x

    PubMed  Google Scholar 

  • Kahn DA, Baltimore D (2010) Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance. Proc Natl Acad Sci U S A 107:9299–9304. doi:10.1073/pnas.1003909107

    PubMed  CAS  Google Scholar 

  • Kapitonov VV, Jurka J (2005) RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons. PLoS Biol 3:e181. doi:10.1371/journal.pbio.0030181

    PubMed  Google Scholar 

  • Kasahara M (2000) Genome paralogy: A new perspective on the organization and origin of the major histocompatibility complex. Curr Top Microbiol Immunol 248:53–66

    PubMed  CAS  Google Scholar 

  • Kassiotis G, O’Garra A (2009) Establishing the follicular helper identity. Immunity 31:450–452. doi:10.1016/j.immuni.2009.08.017

    PubMed  CAS  Google Scholar 

  • Kim MY (2008) Roles of embryonic and adult lymphoid tissue inducer cells in primary and secondary lymphoid tissues. Yonsei Med J 49:352–356. doi:10.3349/ymj.2008.49.3.352

    PubMed  CAS  Google Scholar 

  • Kim MY, Kim KS, McConnel F, Lane P (2009) Lymphoid tissue inducer cells: architects of CD4 immune responses in mice and men. Clin Exp Immunol 157:20–26. doi:10.1111/j.1365-2249.2009.03932.x

    PubMed  CAS  Google Scholar 

  • Koh AS, Kuo AJ, Park SY, Cheung P, Abramson J, Bua D, Carney D, Shoelson SE, Gozani O, Kingston RE, Benoist C, Mathis D (2008) Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc Natl Acad Sci U S A 105:15878–15883. doi:10.1073/pnas.0808470105

    PubMed  CAS  Google Scholar 

  • Kosak ST, Groudine M (2004) Form follows function: the genomic organization of cellular differentiation. Genes Dev 18:1371–1384. doi:10.1101/gad.1209304

    PubMed  CAS  Google Scholar 

  • Kosak ST, Skok JA, Medina KL, Riblet R, Le Beau MM, Fisher AG, Singh H (2002) Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 296:158–162. doi:10.1126/science.1068768

    PubMed  CAS  Google Scholar 

  • Kosak ST, Scalzo D, Alworth SV, Li F, Palmer S, Enver T, Lee JS, Groudine M (2007) Coordinate gene regulation during hematopoiesis is related to genomic organization. PLoS Biol 5:e309. doi:10.1371/journal.pbio.0050309

    PubMed  Google Scholar 

  • Kyewski B, Klein L (2006) A central role for central tolerance. Annu Rev Immunol 24:571–606. doi:10.1146/annurev.immunol.23.021704.115601

    PubMed  CAS  Google Scholar 

  • Levy O, Zarember KA, Roy RM, Cywes C, Godowski PJ, Wessels MR (2004) Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848. J Immunol 173:4627–4634

    PubMed  CAS  Google Scholar 

  • Lin YC, Jhunjhunwala S, Benner C, Heinz S, Welinder E, Mansson R, Sigvardsson M, Hagman J, Espinoza CA, Dutkowski J, Ideker T, Glass CK, Murre C (2010) A global network of transcription factors, involving E2A, EBF1 and Fox1, that orchestrates the B cell fate. Nat Immunol 11:635–643. doi:10.1038/ni.1891

    PubMed  CAS  Google Scholar 

  • Linch DC, Knott LJ, Rodeck CH, Huehns ER (1982) Studies of circulating hemopoietic progenitors in human fetal blood. Blood 59:976–979

    PubMed  CAS  Google Scholar 

  • Liu H, Schmidt-Supprian M, Shi Y, Hobeika E, Barteneva N, Jumaa H, Pelanda R, Reth M, Skok J, Rajewsky K, Shi Y (2007) Yin Yang 1 is a critical regulator of B-cell development. Genes Dev 21:1179–1189. doi:10.1101/gad.1529307

    PubMed  CAS  Google Scholar 

  • Manavalan B, Basith S, Choi S (2011) Similar structures but different roles – an updated perspective on TLR structure. Front Physiol 2:41. doi:10.3389/fphys.2011.00041

    PubMed  Google Scholar 

  • Marchant A, Appay V, Van Der Sande M, Dulphy N, Liesnard C, Kidd M, Kaye S, Ojuola O, Gillespie GM, Vargas Cuero AL, Cerundolo V, Callan M, McAdam KP, Rowland-Jones SL, Donner C, McMichael AJ, Whittle H (2003) Mature CD8(+) T lymphocyte response to viral infection during fetal life. J Clin Invest 111:1747–1755. doi:10.1172/JCI17470

    PubMed  CAS  Google Scholar 

  • Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD, Levine SS, Fraenkel E, von Boehmer H, Young RA (2007) Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445:931–935. doi:10.1038/nature05478

    PubMed  CAS  Google Scholar 

  • Mays LE, Chen YH (2007) Maintaining immunological tolerance with Foxp3. Cell Res 17:904–918. doi:10.1038/cr.2007.84

    PubMed  CAS  Google Scholar 

  • Migliaccio G, Migliaccio AR, Petti S, Mavilio F, Russo G, Lazzaro D, Testa U, Marinucci M, Peschle C (1986) Human embryonic hemopoiesis. Kinetics of progenitors and precursors underlying the yolk sac to liver transition. J Clin Invest 78:51–60. doi:10.1172/JCI112572

    PubMed  CAS  Google Scholar 

  • Miyamoto T, Akashi K (2005) Lineage promiscuous expression of transcription factors in normal hematopoiesis. Int J Hematol 81:361–367. doi:10.1532/IJH97.05003

    PubMed  CAS  Google Scholar 

  • Mostoslavsky R, Singh N, Kirillov A, Pelanda R, Cedar H, Chess A, Bergman Y (1998) Kappa chain monoallelic demethylation and the establishment of allelic exclusion. Genes Dev 12:1801–1811. doi:10.1101/gad.12.12.1801

    PubMed  CAS  Google Scholar 

  • Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM, Kung AL, Cereb N, Yao TP, Yang SY, Reiner SL (2001) Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292:1907–1910. doi:10.1126/science.1059835

    PubMed  CAS  Google Scholar 

  • Murre C (2007) Epigenetics of antigen-receptor assembly. Curr Opin Genet Dev 17:415–421. doi:10.1016/j.gde.2007.08.006

    PubMed  CAS  Google Scholar 

  • Niller HH, Salamon D, Rahmann S, Ilg K, Koroknai A, Bánáti F, Schwarzmann F, Wolf H, Minárovits J (2004) A 30 kb region of the Epstein-Barr virus genome is colinear with the rearranged human immunglobulin gene loci: Implications for a “ping-pong” evolution model for persisting viruses and their hosts. Acta Microbiol Immunol Hung 51:469–484. doi:10.1556/AMicr.51.2004.4.7

    PubMed  CAS  Google Scholar 

  • Nossal GJV (1991) Molecular and cellular aspects of immunologic tolerance. Eur J Biochem 202:729–737. doi:10.1111/j.1432-1033.1991.tb16427.x

    PubMed  CAS  Google Scholar 

  • Oettinger MA, Schatz DG, Gorka C, Baltimore D (1990) RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248:1517–1523. doi:10.1126/science.2360047

    PubMed  CAS  Google Scholar 

  • Org T, Chignola F, Hetényi C, Gaetani M, Rebane A, Liiv I, Maran U, Mollica L, Bottomley MJ, Musco G, Peterson P (2008) The autoimmune regulator PHD finger binds to non-methylated histome H3K4 to activate gene expression. EMBO Rep 9:370–376. doi:10.1038/embor.2008.11

    PubMed  CAS  Google Scholar 

  • Ottersbach K, Dzierzak E (2010) The placenta as a haematopoietic organ. Int J Dev Biol 54:1099–1106. doi:10.1387/ijdb.093057ko

    PubMed  Google Scholar 

  • Oven I, Brdicková N, Kohoutek J, Vaupotic T, Narat M, Peterlin BM (2007) AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. Mol Cell Biol 27:8815–8823. doi:10.1128/MCB.01085-07

    PubMed  CAS  Google Scholar 

  • Parra M (2009) Epigenetic events during B lymphocyte development. Epigenetics 4:462–468. doi:10.4161/epi.4.7.10052

    PubMed  CAS  Google Scholar 

  • Pedra JH, Cassel SL, Sutterwala FS (2009) Sensing pathogens and danger signals by the inflammasome. Curr Opin Immunol 21:10–16. doi:10.1016/j.coi.2009.01.006

    PubMed  CAS  Google Scholar 

  • Peterson P, Org T, Rebane A (2008) Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol 8:948–957. doi:10.1038/nri2450

    PubMed  CAS  Google Scholar 

  • Philbin VJ, Levy O (2009) Developmental biology of the innate immune response: implications for neonatal and infant vaccine development. Pediatr Res 65:98R–105R. doi:10.1203/PDR.0b013e31819f195d

    PubMed  Google Scholar 

  • Pitkin RM, Reynolds WA (1975) Fetal ingestion and metabolism of amniotic fluid protein. Am J Obstet Gynecol 15:356–363

    Google Scholar 

  • Pridans C, Holmes ML, Polli M, Wettenhall JM, Dakic A, Corcoran LM, Smyth GK, Nutt SL (2008) Identification of Pax5 target genes in early B cell differentiation. J Immunol 180:1719–1728

    PubMed  CAS  Google Scholar 

  • Rajapaske I, Perlman MD, Scalzo D, Kooperberg C, Groudine M, Kosak ST (2009) The emergence of lineage-specific chromosomal topologies from coordinate gene regulation. Proc Natl Acad Sci U S A 106:6679–6684. doi:10.1073/pnas.0900986106

    Google Scholar 

  • Ringrose L, Paro R (2007) Polycomb/Trithorax response elements and epigenetic memory of cell identity. Development 134:223–232. doi:10.1242/dev.02723

    PubMed  CAS  Google Scholar 

  • Robin C, Bollerot K, Mendes S, Haak E, Crisan M, Cerisoli F, Lauw I, Kaimakis P, Jorna R, Vermeulen M, Kayser M, van der Linden R, Imanirad P, Verstegen M, Nawaz-Yousaf H, Papazian N, Steegers E, Cupedo T, Dzierzak E (2009) Human placenta is a potential hematopoietic niche containing hematopoietic stem and progenitor cells throughout development. Cell Stem Cell 5:385–395. doi:10.1016/j.stem.2009.08.020

    PubMed  CAS  Google Scholar 

  • Rogers AM, Boime I, Connolly J, Cook JR, Russell JH (1998) Maternal-fetal tolerance is maintained despite transgene-driven trophoblast expression of MHC class I, and defects in Fas and its ligand. Eur J Immunol 28:3479–3487. doi:10.1002/(SICI)1521-4141(199811)28:11<3479::AID-IMMU3479>3.0.CO;2-U

    PubMed  CAS  Google Scholar 

  • Roldán E, Fuxa M, Chong W, Martinez D, Novatchkova M, Busslinger M, Skok JA (2005) Locus ‘decontraction’ and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nat Immunol 6:31–41. doi:10.1038/ni1150

    PubMed  Google Scholar 

  • Rothenberg EV (2007) Cell lineage regulators in B and T development. Nat Immunol 8:441–444. doi:10.1038/ni1461

    PubMed  CAS  Google Scholar 

  • Sakano H, Hüppi K, Heinrich G, Tonegawa S (1979) Sequences at the somatic recombination sites of immunoglobulin light-chai genes. Nature 280:288–294. doi:10.1038/280288a0

    PubMed  CAS  Google Scholar 

  • Sayegh CE, Jhunjhunwala S, Riblet R, Murre C (2005) Visualization of looping involving the immunoglobulin heavy-chain locus in developing B cells. Genes Dev 19:322–327. doi:10.1101/gad.1254305

    PubMed  CAS  Google Scholar 

  • Scheffold A, Hühn J, Höfer T (2005) Regulation of CD4 + CD25+ regulatory T cell activity: it takes (IL-) two to tango. Eur J Immunol 35:1336–1341. doi:10.1002/eji.200425887

    PubMed  CAS  Google Scholar 

  • Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF (2001) Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 276:37672–37679. doi:10.1074/jbc.M104521200

    PubMed  CAS  Google Scholar 

  • Smith E, Sigvardsson M (2004) The roles of transcription factors in B lymphocyte commitment, development, and transformation. J Leukoc Biol 75:973–981. doi:10.1189/jlb.1103554

    PubMed  CAS  Google Scholar 

  • Spencer J, MacDonald TT, Finn T, Isaacson PG (1986) The development of gut associated lymphoid tissue int he terminal ileum of fetal human intestine. Clin Exp Immunol 64:536–543

    PubMed  CAS  Google Scholar 

  • Stanlie A, Aida M, Muramatsu M, Honjo T, Begum NA (2010) Histone3 lysine4 trimethylation regulated by the facilitates chromatin transcription complex is critical in class switch recombination. Proc Natl Acad Sci U S A 107:22190–22195. doi:10.1073/pnas.1016923108

    PubMed  CAS  Google Scholar 

  • Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, Walker JR, Hogenesch JB (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 101:6062–6067. doi:10.1073/pnas.0400782101

    PubMed  CAS  Google Scholar 

  • Szekeres-Bartho J, Balasch J (2008) Progestagen therapy for recurrent miscarriage. Hum Reprod Update 14:27–35. doi:10.1093/humupd/dmm035

    PubMed  Google Scholar 

  • Szépfalusi Z, Pichler J, Elsässer S, van Duren K, Ebner C, Bernaschek G, Urbanek R (2000) Transplacental priming of the human immune system with environmental allergen can occur early in gestation. J Allergy Clin Immunol 106:530–536. doi:10.1067/mai.2000.108710

    PubMed  Google Scholar 

  • Taglauer ES, Adams Waldorf KM, Petroff MG (2010) The hidden maternal-fetal interface: events involving the lymphoid organs in maternal-fetal tolerance. Int J Dev Biol 54:421–430. doi:10.1387/ijdb.082800et

    PubMed  CAS  Google Scholar 

  • Tagoh H, Ingram R, Wilson N, Salvagiotto G, Warren AJ, Clarke D, Busslinger M, Bonifer C (2006) The mechanism of repression of the myeloid-specific c-fms gene by Pax5 during B lineage restriction. EMBO J 25:1070–1080. doi:10.1038/sj.emboj.7600997

    PubMed  CAS  Google Scholar 

  • Thompson CB (1995) New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 3:531–539. doi:10.1016/1074-7613(95)90124-8

    PubMed  CAS  Google Scholar 

  • Vermijlen D, Brouwer M, Donner C, Liesnard C, Tackoen M, Van Rysselberge M, Twité N, Goldman M, Marchant A, Willems F (2010) Human cytomegalovirus elicits fetal γδ T cell responses in utero. J Exp Med 207:807–821. doi:10.1084/jem.20090348

    PubMed  CAS  Google Scholar 

  • Villaseñor J, Besse W, Benoist C, Mathis D (2008) Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. Proc Natl Acad Sci U S A 105:15854–15859. doi:10.1073/pnas.0808069105

    PubMed  Google Scholar 

  • Walter K, Bonifer C, Tagoh H (2008) Stem cell-specific epigenetic priming and B cell-specific transcriptional activation at the mouse Cd19 locus. Blood 112:1673–1682. doi:10.1182/blood-2008-02-142786

    PubMed  CAS  Google Scholar 

  • Wilson CB, Makar K, Pérez-Melgosa M (2002) Epigenetic regulation of T cell fate and function. J Infect Dis 185(Suppl 1):S37–S45. doi:10.1086/338001

    PubMed  CAS  Google Scholar 

  • Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, Bates DL, Guo L, Han A, Ziegler SF, Mathis D, Benoist C, Chen L, Rao A (2006) FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126:375–387. doi:10.1016/j.cell.2006.05.042

    PubMed  CAS  Google Scholar 

  • Xu J, Pope SD, Jazirehi AR, Attema JL, Papathanasiou P, Watts JA, Zaret KS, Weissman IL, Smale ST (2007) Pioneer factor interactions and unmethylated CpG dinucleotides mark silent tissue-specific enhancers in embryonic stem cells. Proc Natl Acad Sci U S A 104:12377–12382. doi:10.1073/pnas.0704579104

    PubMed  CAS  Google Scholar 

  • Xu J, Watts JA, Pope SD, Gadue P, Kamps M, Plath K, Zaret KS, Smale ST (2009) Transcriptional competence and active marking of tissue-specific enhancers by defined transcription factors in embryonic and induced pluripotent stem cells. Genes Develop 23:2824–2838. doi:10.1101/gad.1861209

    PubMed  CAS  Google Scholar 

  • Yan SR, Qing G, Byers DM, Stadnyk AW, Al-Hertani W, Bortolussi R (2004) Role of MyD88 in diminished tumor necrosis factor alpha production by newborn mononuclear cells in response lipopolysaccharide. Infect Immun 72:1223–1229. doi:10.1128/IAI.72.3.1223-1229.2004

    PubMed  CAS  Google Scholar 

  • Yancopoulos GD, Alt FW (1985) Developmentally controlled and tissue-specific expression of unrearranged VH gene segments. Cell 40:271–281. doi:10.1016/0092-8674(85)90141-2

    PubMed  CAS  Google Scholar 

  • Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL, Srivastava M, Linterman M, Zheng L, Simpson N, Ellyard JI, Parish IA, Ma CS, Li QJ, Parish CR, Mackay CR, Vinuesa CG (2009) The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31:457–468. doi:10.1016/j.immuni.2009.07.002

    PubMed  CAS  Google Scholar 

  • Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY (2007) Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445:936–940. doi:10.1038/nature05563

    PubMed  CAS  Google Scholar 

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  1. Microbiological Research Group, National Center for Epidemiology, Piheno u. 1, H-1529, Budapest, Hungary

    Eva Ay, Krisztina Buzas, Ferenc Banati & Janos Minarovits

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  1. Eva Ay
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  2. Krisztina Buzas
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  3. Ferenc Banati
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Correspondence to Janos Minarovits .

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  1. , Division of Virology, National Center for Epidemiology, Gyáli Street 2-6, Budapest, 1096, Hungary

    György Berencsi III

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Ay, E., Buzas, K., Banati, F., Minarovits, J. (2012). Recent Results on the Development of Fetal Immune System: Self, Epigenetic Regulation, Fetal Immune Responses. In: Berencsi III, G. (eds) Maternal Fetal Transmission of Human Viruses and their Influence on Tumorigenesis. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4216-1_2

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